Niche Cells and Signals that Regulate Lung Alveolar Stem Cells In Vivo

Abstract

The distal lung is a honeycomb-like collection of delicate gas exchange sacs called alveoli lined by two interspersed epithelial cell types: the cuboidal, surfactant-producing alveolar type II (AT2) and the flat, gas-exchanging alveolar type I (AT1) cell. During aging, a subset of AT2 cells expressing the canonical Wnt target gene, Axin2, function as stem cells, renewing themselves while generating new AT1 and AT2 cells. Wnt activity endows AT2 cells with proliferative competency, enabling them to respond to activating cues, and simultaneously blocks AT2 to AT1 cell transdifferentiation. Acute alveolar injury rapidly expands the AT2 stem cell pool by transiently inducing Wnt signaling activity in "bulk" AT2 cells, facilitating rapid epithelial repair. AT2 cell "stemness" is thus tightly regulated by access to Wnts, supplied by a specialized single-cell fibroblast niche during maintenance and by AT2 cells themselves during injury repair. Two non-AT2 "reserve" cell populations residing in the distal airways also contribute to alveolar repair, but only after widespread epithelial injury, when they rapidly proliferate, migrate, and differentiate into airway and alveolar lineages. Here, we review alveolar renewal and repair with a focus on the niches, rather than the stem cells, highlighting what is known about the cellular and molecular mechanisms by which they control stem cell activity in vivo.

Figure 1.

Anatomic domains and cellular microenvironments for alveolar progenitor cells. The three best-characterized alveolar stem and progenitor cells are schematized within the distal lung (left) with a close-up of the microenvironment in which each resides (right). (AT2) Alveolar epithelial type II cell, (BASC) bronchioalveolar stem cell, (LNEP/DASC) lineage-negative epithelial progenitor/distal airway stem cell, (A) alveolar, (I) interstitial.

Figure 2.

Signaling between alveolar stem and niche cells operative in specific experimental perturbations and contexts. (Top left) Panel summarizes each color-coded cell type and its position relative to the stem cells. Each additional panel schematizes the molecular signals and their sources that impact on the stem cell. The arrows are coded to indicate specific effects on the stem cell (legend below the panels), and the box outlining each panel is color-coded to indicate the experimental context in which the signaling is operative (maintenance; repair; pneumonectomy). (AT1) Alveolar epithelial type I, (AT2) alveolar epithelial type II, (BASC) bronchioalveolar stem cell, (Endo) endothelial cell, (FB) fibroblast, (LNEP/DASC) lineage-negative epithelial progenitor/distal airway stem cell, (L-cyte) lymphocyte, (AM) alveolar macrophage, (M2) M2 polarized macrophage, (Mono) monocyte, (PC) pericyte, (ASM) airway smooth muscle cell, (VSM) vascular smooth muscle, (?) unknown signal(s).

Figure 3.

Dynamic signaling in alveolar stem cells that sequentially drive proliferation and differentiation. Signaling pathway activity (dark shade indicates active) in alveolar type II (AT2) cells (top) and LNEP/DASC cells (bottom) during sequential steps of their regenerative programs. “Stem” indicates Axin2⁺ and “Bulk” indicates Axin2⁻ AT2 cells. Dashed outlines represent dying cells.

Figure 4.

Lung adenocarcinoma “tumor niche.” Tumor-associated cells and the signals they produce that have been shown to confer proliferative competence (yellow arrows) and augment proliferation (green arrow) of epithelial tumor cells in Kras-driven lung adenocarcinoma. (FB) Fibroblast, (γδ) γδ T cell, (M2Φ) alternately activated macrophage, (?) unknown signal(s).